Abstract / Summary
Background/Objectives: Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lacrimal and salivary gland dysfunction, leading to dry eye and dry mouth. This study aimed to explore the potential associations between oxidative stress-mediated immune and apoptotic responses in Sjögren’s syndrome dry eye (SSDE) and to computationally predict theoretical interacting candidates. Methods: We enrolled 16 SSDE patients and 15 healthy controls to assess key clinical parameters. The study utilized conjunctival impression cytology, RNA-seq, and bioinformatics to identify exploratory transcriptomic signatures. Gene expression levels were then assessed using real-time quantitative PCR (RT-qPCR). To provide supportive cross-species biological context regarding local oxidative stress status in vivo, malondialdehyde (MDA) levels were quantified in the extraorbital lacrimal glands of an SSDE murine model (NOD mice vs. BALB/c controls, n = 6/group). Furthermore, molecular docking and 100 ns molecular dynamics simulations were conducted to computationally explore potential pharmacological interventions. Results: Exploratory global transcriptomic analysis indicated that differentially expressed genes (DEGs) were prominently enriched in immune responses, inflammatory signaling, and apoptotic pathways, aiding the identification of a candidate transcriptomic signature of oxidative stress-related DEGs. Preliminary immune infiltration profiling suggested that the abundance levels of CD4+ T cells and eosinophils were positively correlated, while M1 and M2 macrophages were negatively correlated. Exploratory ROC analysis suggested the potential discriminative value (AUC 0.7–0.9) for key disease-associated genes, notably CDKN1A and BAX (r = 0.883). RT-qPCR results demonstrated that the transcription levels of CDKN1A, BAX, TGFBR1, and S100A9 were significantly higher in the SSDE group compared to the healthy control group (p < 0.05). Importantly, in vivo biochemical assays provided supportive cross-species evidence of lipid peroxidation, demonstrating a significant elevation in MDA levels in the lacrimal glands of NOD mice compared to controls (p < 0.01). Furthermore, in silico molecular simulations suggested that natural antioxidants, such as ursolic acid and andrographolide, exhibited favorable predicted binding conformations within the active pockets of CDKN1A and BAX. Conclusions: Supported by exploratory transcriptomic profiling and supportive in vivo biochemical data, our findings highlight an exploratory molecular association between oxidative stress and an intimately coupled immune–apoptotic axis in SSDE pathogenesis. The computational structural evaluation of ursolic acid and andrographolide provides a hypothesis-generating foundation for future in vitro and in vivo pharmacological investigations.